This invention relates to novel substituted aminotetralins useful as 5-HT1D agonists.
Over the last several years it has become apparent that serotonin (5-hydroxytryptamine; 5-HT) is associated directly or indirectly with a number of physiological phenomena, including appetite, memory, thermo-regulation, sleep, sexual behavior, anxiety, depression, and hallucinogenic behavior [Glennon, R. A., J. Med. Chem. 30, 1 (1987)].
5-HT receptors have been identified in the central nervous system (CNS; brain and spinal cord) and in peripheral tissues including the gastrointestinal tract, lung, heart, blood vessels, and various other smooth muscle tissues.
It has been recognized that there are multiples types of 5-HT receptors. These receptors have been classificed as 5-HT1, 5-HT2 and 5-HT3 receptors, with the former being further divided into the sub-classes 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT1E, and 5-HT1F.
Within the 5-HT1 receptor class, several subtypes have been distinguished on the basis of their pharmacological binding profiles, second messenger coupling and physiological roles. One such subtype, the 5-HT1D receptor, was originally defined as a particular type of [3H]5-HT binding site in the bovine caudate (Heuring and Peroutka, J. Neurosci., 7:894 (1987)).
Few ligands have selectivity for 5-HT1D receptors. Sumatriptan possesses limited 5-HT1D selectivity. GR 127935 has also been identified as a patent and selective 5-HT1D receptor antagonist. Hayer, et al., Pharmacological Reviews, Vol. 46, No. 2, pp. 157-203 (1994).
Molecular cloning has demonstrated that pharmacologically defined 5-HT1D receptors are encloded by two separate but closely related genes, designated 5-HT1Dxcex1 and 5-HT1Dxcex2, which are members of the GPRC superfamily. These receptors display highly conserved transmembrane homology (75%) and similar binding properties and second messenger coupling (inhibition of adenylate cyclase). Leonhardt, S., et al., J. Neurochem, 53:465-471 (1989).
The 5-HT1Dxcex1 receptor is a species homolog of the 5-HT1D receptor of bovine calif caudate and guinea-pig brain. Hartig, et al., supra.
The 5-HT1B and 5-HT1Dxcex2 receptors have recently been shown to be species homologues of the same receptor subtype. They display similarities in their pharmacology, second messenger coupling, and anatomical distribution. The 5-HT1B subtype appears to be confined to rat, mouse, and opossum whereas 5-HT1Dxcex2 sites have been demonstrated in human, pig, guinea pig and calf. Adham, N., et al., Mol. Pharmacol., 41:1-7 (1992).
The rat 5-HT1B receptor differs from its human counterpart at only 4% of its transmembrane amino acids, but its pharmacological binding properties are dramatically different from those of the human 5-HT1DB receptor. Hartig, et al., Trends Pharmacol. Sci., 13:152-159 (1992).
We have now discovered a further class of compounds which have selective 5-HT1Dxcex1 agonist activity useful in treatment of dementia, Parkinson""s Disease, appetite modulation, anxiety, migraine, sexual dysfunction, irritative bladder symptoms of benign prostatic hyperplasia, urge incontinence and excessive bladder activity caused by bacterial cystitis, interstitial cystitis, radiation/chemotherapy-induced cystitis, outlet obstruction, neurogenic bladder, spinal cord injury, stroke, and nocturnal enurisis.
It is desirable to develop new compounds and treatments for these 5-HT1Dxcex1 mediated diseases.
This invention provides a compound of formula I 
wherein:
R1 and R2 are each individually hydrogen or xe2x80x94(C1-C6)alkyl;
R3 is xe2x80x94(C2-C8)alkenyl, xe2x80x94(CH2)q(C3-C8)cycloalkyl xe2x80x94(CH2)nO(CH2)pR5, 
xe2x80x83or 
xe2x80x83substituted with one substituent selected from the group consisting of xe2x80x94(C1-C6)alkyl and xe2x80x94(C3-C8)cycloalkyl;
xe2x80x83where
Axe2x80x94B is  greater than Cxe2x95x90CHxe2x80x94 or  greater than CR4CH2xe2x80x94;
D is xe2x80x94CH2xe2x80x94 or oxygen;
R4 is hydrogen or xe2x80x94OH;
R5xe2x80x2 is xe2x80x94(C3-C8)cycloalkyl, or phenyl substituted with one substituent selected from the group consisting of halo, xe2x80x94(C1-C6)alkyl and (C1-C6)alkoxy;
m is an integer from 1 to 5 both inclusive;
n is an integer from 0 to 4 both inclusive;
p is an integer from 1 to 7 both inclusive; and
q is an integer from 0 to 4 both inclusive;
or a pharmaceutically acceptable salt or optical isomer thereof;
provided that when D is oxygen,  greater than Axe2x80x94B is not  greater than Cxe2x95x90CHxe2x80x94; and when R4 is xe2x80x94OH, D is oxygen.
This invention also provides a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluents, carriers and excipients.
This invention further provides a method of activating the 5-HT1Dxcex1 receptor comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula II 
wherein:
R1 and R2 are each individually hydrogen or xe2x80x94(C1-C6)alkyl;
R3xe2x80x2 is xe2x80x94(C1-C8)alkyl, xe2x80x94(CH2)q(C3-C8)cycloalkyl, xe2x80x94(C2-C8)alkenyl, xe2x80x94(C1-C8)alkan-1-ol-1-yl, xe2x80x94(CH2)nO(CH2)pR5xe2x80x2, 
xe2x80x83or 
xe2x80x83substituted with one substituent selected from the group consisting of xe2x80x94(C1-C6)alkyl and xe2x80x94(C3-C8)cycloalkyl;
xe2x80x83where
Axe2x80x94B is  greater than Cxe2x95x90CHxe2x80x94 or  greater than CR4CH2xe2x80x94;
D is xe2x80x94CH2xe2x80x94 or oxygen;
R4 is hydrogen or xe2x80x94OH;
R5xe2x80x2 is xe2x80x94(C1-C6)alkyl, xe2x80x94(C3-C8)cycloalkyl, xe2x80x94(C1-C6)alkoxy, phenyl or phenyl substituted with one substituent. selected from the group consisting of halo, xe2x80x94(C1-C6)alkyl and (C1-C6)alkoxy;
m is an integer from 1 to 5 both inclusive;
n is an integer from 0 to 4 both inclusive;
p is an integer from 1 to 7 both inclusive; and
q is an integer from 0 to 4 both inclusive;
or a pharmaceutically acceptable salt or optical isomer thereof;
provided that when D is oxygen,  greater than Axe2x80x94B is not  greater than Cxe2x95x90CHxe2x80x94.
This invention also provides a method of alleviating the pathological effects of 5-HT1Dxcex1 receptor-activated diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula II.
A still further aspect of the invention is a method of treating a mammal suffering from or susceptible to any condition activated by the 5HT1Dxcex1 receptor of the type represented by dementia, Parkinson""s disease, anxiety, migraine, appetite modulation, sexual dysfunction, irritative bladder symptoms of benign prostatic hyperplasia, urge incontinence and excessive bladder activity caused by bacterial cystitis, interstitial cystitis, radiation/chemotherapy-induced cystitis, outlet obstruction, neurogenic bladder, spinal cord injury, stroke and nocturnal enurisis which comprises administering to said mammal a therapeutically-effective amount of a compound of formula (II).
Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
Definitions
As used herein, the term, xe2x80x9c(C1-C8)alkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl and the like. The term xe2x80x9c(C1-C8)alkylxe2x80x9d encompasses xe2x80x9c(C1-C6)alkylxe2x80x9d.
The term xe2x80x9chaloxe2x80x9d means chloro, fluoro, bromo or iodo.
The term xe2x80x9c(C1-C6)alkoxyxe2x80x9d denotes a straight or branched alkyl chain having one to six carbon atoms attached to the remainder of the molecule by an oxygen atom. Typical (C1-C6) alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, isopentoxy, neopentoxy and the like.
The term xe2x80x9c(C3-C8) cycloalkylxe2x80x9d referes to a hydrocarbon ring having the stated number of carbon atoms. Typical (C3-C8) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
The term, xe2x80x9c(C2-C8)alkenyl,xe2x80x9d as used herein, means a straight chain or branched monovalent hydrocarbon group attached to the tetralin ring at any point on the chain, having the stated number range of carbon atoms and one double bond on the carbon attached to the tetralin ring. Typical groups include vinyl, prop-1-en-1-yl, isoprop-1-en-1-yl, n-but-2-en-2-yl, tertiary but-1-en-1-yl, isobut-1-en-1-yl, n-pent-1-en-1-yl, isopent-1-en-1-yl, pent-1-en-1-yl, hept-3-en-3-yl, hex-2-en-2-yl, oct-2-en-2-yl and the like.
The term, xe2x80x9c(C1-C8)alkan-1-ol-1-ylxe2x80x9d means a straight or branched chain monovalent hydrocarbon radical having the stated number of carbon atoms attached to the tetralin ring at the 1-position of the chain and, further, having an hydroxy group attached to the 1-position of the chain. Such groups include methan-1-ol-1-yl, ethan-1-ol-1-yl, n-propan-1-ol-1-yl, isopropan-ol-1-yl, n-butan-1-ol-1-yl, tertiary butan-1-ol-1-yl, isobutan-1-ol-1-yl, sec-butan-1-ol-1-yl, n-pentan-1-ol-1-yl, isopentan-1-ol-1-yl, neopentan-1-ol-1-yl, heptan-1-ol-1-yl, hexan-1-ol-1-yl, octan-1-ol-1-yl and the like.
Useful compounds for practicing the present invention includes pharmaceutically acceptable acid addition salts of the compounds defined by the above formulae I and II. Since the compounds of formula I are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts.
Acids commonly employed to form such salts are inorganic acids, such as hydrocholoric acid, hydrobomic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosolfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogensphosphate, dihydrogenphosphate, metaphosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumariate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, y-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid.
The compounds of the instant invention may have one stereocenter at the 2-position, and possibly more stereocenters, depending on the R3 substituent at the 8-position, and may be isolated in optically active and racemic forms. The optically active isomers of the racemates of invention are also considered within the scope of Formulae I and II. Such optically active isomers may be prepared from their respective optically active precursors following the procedure described below, or by resolving the racemic mixtures. These resolutions can typically be carried out in the presence of a resolving agent, by chromatography or by repeated cyrstallization.
Procedures for separating racemates into their individual isomers can be found in references such as Jacques, et al., Enantiomers, Racemates and Resolutions, (John Wiley and Sons, New York 1981).
The term xe2x80x9camino-protecting groupxe2x80x9d is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent an amino group from participating in a reaction carried out on some other functional group of the molecule, but which can be removed from the amine when it is desired to do so. In a similar fashion, the term xe2x80x9chydroxy protecting groupxe2x80x9d refers to a removable group which will prevent a hydroxy group from participating in a reaction performed on the molecule. Such groups are discussed by T. W. Greene in chapters 2 and 7 of Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981, and by J. W. Barton in chapter 2 of Protective Groups in Organic Chemistry, J. F. W. McOmie, ed., Plenum Press, New York, 1973, which are incorporated herein by reference in their entirety. Examples of amino protecting groups include benzyl and substituted benzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl; those of the formula xe2x80x94COOR where R includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1-methyl-1-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, and p-methoxybenzoyl; and other groups such as methanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl, p-nitrophenylethyl, and p-toluenesulfonylaminocarbonyl. A preferred amino-blocking group is t-butoxycarbonyl.
Examples of hydroxy protecting groups include ether and substituted ether forming groups such as methyl, methoxymethyl, t-butoxymethyl, 1-ethoxyethyl and benzyl; silyl ether forming groups such as trimethylsilyl, triethylsilyl and methyl-diisopropylsilyl; ester forming groups such as formate, acetate and trichloroacetate and carbonate groups, such as methyl, 2,2,2-trichloroethylcarbonate and p-nitrophenyl carbonates.
The term xe2x80x9curinary incontinencexe2x80x9d includes bacterial cystitis, interstitial cystitis, radiation/chemotherapy induced cystitis, outlet obstruction, neurogenic bladder, incontinence due to spinal cord injury and stroke, and nocturnal enurisis.
Preferred substituent groups of compounds of formulae I and II include the following:
(a) R1 and R2 are each independently hydrogen;
(b) R1 and R2 are each independently xe2x80x94(C1-C6)alkyl;
(c) R3 is xe2x80x94(C1-C8)alkyl;
(d) R3 is xe2x80x94(CH2)nO(CH2)pR5;
(e) R3 is xe2x80x94(C2-C8)alkenyl; 
(f) R3 is
(g) R3 is 
xe2x80x83substituted with one substituent selected from the group consisting of xe2x80x94(C1-C6)alkyl or xe2x80x94(C3-C8)cycloalkyl;
(h) R5 is xe2x80x94(C3-C8)cycloalkyl;
(i) R5 is phenyl substituted with one substituent selected from the group consisting of xe2x80x94(C1-C6)alkyl or (C1-C6)alkoxy;
(j) R5 is phenyl substituted with halo;
(k) Axe2x80x94B is  greater than Cxe2x95x90CHxe2x80x94;
(l) Axe2x80x94B is  greater than CR4CH2xe2x80x94;
(m) D is CH2;
(n) D is oxygen;
(o) m is 2-4;
(p) n is 1;
(q) p is 2; and
(r) q is 0 or 1.
A preferred genus of compounds include those compounds of formula I where:
R1 and R2 are each individually hydrogen or xe2x80x94(C1-C6)alkyl;
R3 is 
xe2x80x83and
m is 2 or 3.
Of this preferred genus, compounds where Axe2x80x94B is  greater than Cxe2x95x90CHxe2x80x94 are more preferred.
Still another preferred group of compounds include those where Axe2x80x94B is  greater than CR4CH2xe2x80x94 and D is xe2x80x94CH2xe2x80x94.
The most preferred compound of the instant invention is 2-N,N-dimethylamino-8-(2-methylcyclopent-1-yl)tetralin hydrochloride.
Further typical examples of compounds of formula I which are useful in the present invention include:
2-N-methylamino-8-ethyltetralin;
2-N,N-dipropylamino-8-isopropyltetralin;
2-N-methyl-N-ethyl-8-pentyltetralin;
2-N,N-di-t-butylamino-8-isobutyltetralin;
2-N-ethyl-N-hexyl-8-octyltetralin;
2-N,N-dipropylamino-8-methyltetralin;
2-N-butylamino-8-eth-1-en-1-yltetralin;
2-N,N-dimethylamino-8-isoprop-1-en-1-yltetralin;
2-N-ethyl-N-methyl-8-but-1-en-1-yltetralin;
2-N,N-diethylamino-8-pent-1-en-1-yltetralin;
2-N-propylamino-8-hept-1-en-lyltetralin;
2-N-methyl-N-butyl-8-cyclopropylmethyloxymethyltetralin;
2-N,N-di-t-butyl-8-(2-cyclobutylethyl)oxymethyltetralin;
2-N-pentylamino-8-(2-(3-cyclopentylpropyl)oxy)ethyltetralin;
2-N-methyl-N-hexyl-8-(4-cyclohexylbutyl)oxytetralin;
2-N-methyltetralin-8-(4-(7-cyclooctylheptyl)oxy)butyltetralin;
2-N,N-dimethylamino-8-(3-(3-chlorophenyl)propyl)oxymethyltetralin;
2-N-ethyl-N-methylamino-8-(4-(4-methylphenyl)butyl)oxytetralin;
2-N-pentylamino-8-(3-(2-methoxyphenyl)methyloxy)propyltetralin;
2-N,N-diethylamino-8-(4-(3-(3-fluorophenyl)propyl)oxy)butyltetralin;
2-N-t-butyl-N-methylamino-8-(5-(4-ethylphenyl)pentyl)oxytetralin;
2-N-hexylamino-8-(5-(2-propoxyphenyl)heptyl)oxymethyltetralin;
2-N,N-dipropyl-8-(2-(6-(3-propylphenyl)hexyl)oxy) ethyltetralin;
2-N-methyl-N-butylamino-8-(4-(4-bromophenyl)butyl)oxymethyltetralin;
2-N-isopropylamino-8-(2-(2-hexylphenyl)ethyl)oxymethyltetralin;
2-N,N-diethyl-8-(3-(3-butoxyphenyl)) 2-N-ethyl-N-propylamino-8-cyclobutyltetralin;
2-N-t-butylamino-8-cyclopentyltetralin;
2-N,N-diethylamino-8-cycloheptyltetralin;
2-N-methyl-N-hexylamino-8-cyclooctyltetralin;
2-N-isopentylamino-8-cycloprop-1-en-1-yltetralin;
2,N,N-dibutylamino-8-cyclohex-1-en-1-yltetralin;
2-N-hexyl-N-ethylamino-8-cyclopent-1-en-1-yltetralin;
2-N-isobutylamino-8-(1xe2x80x2-hydroxy)cyclobutyltetralin;
2-N,N-dipentylamino-8(1xe2x80x2-hydroxy)cyclooctyltetralin; and
2-N-propyl-N-methylamino-8-(1xe2x80x2-hydroxy)cycloheptyltetralin.
All of the reactions described in the following schemes are preferably conducted under an inert gas such as nitrogen.
The compounds of formula I where R3 or R3xe2x80x2 is xe2x80x94(C2-C8)alkenyl, 
or 
substituted with xe2x80x94(C1-C6)alkyl or xe2x80x94(C3-C8)cycloalkyl; where Axe2x80x94B is  greater than Cxe2x95x90CHxe2x80x94 or  greater than CR4CH2xe2x80x94 and D is xe2x80x94CH2xe2x80x94 can be prepared according to the following reaction Scheme I. 
one of Ra or Rb is H and the other is xe2x80x94(CH2)q(C3-C8)cycloalkyl, or
Ra and Rb taken together are with the carbon to which they are attached are (C3-C8)alkyl or 
xe2x80x83or substituted 
xe2x80x83where Axe2x80x94B is  greater than CR4CH2xe2x80x94, D is xe2x80x94CH2xe2x80x94 and R4 is xe2x80x94OH;
Rc and Rd taken together with the carbon to which they are attached are (C2-C8)alkenyl or 
xe2x80x83or substituted 
xe2x80x83where Axe2x80x94B is  greater than Cxe2x95x90CHxe2x80x94 and D is xe2x80x94CH2xe2x80x94;
Re is xe2x80x94(C1-C8)alkyl, 
xe2x80x83or substituted 
xe2x80x83where Axe2x80x94B is  greater than CR4CH2xe2x80x94, D is xe2x80x94CH2xe2x80x94 and R4 is hydrogen.
Compound (1), 8-bromo aminotetralin, is first treated with an organo-lithium reagent, preferably n-butyl lithium, to form the activated intermediate (1a). The reaction is carried out in a suitable solvent, preferably tetrahydrofuran or diethylether, at a temperature of about xe2x88x9278xc2x0 C. and is substantially complete in 5 to 60 minutes.
In an aldol reaction, starting at a temperature of about xe2x88x9278xc2x0 C., and gradually allowing to warm to a temperature of about 0xc2x0 C., the lithiated intermediate (1a) is treated with an alkyl ketone or aldehyde or cyclic ketone of the formula RaCORb, where
one of Ra or Rb is hydrogen and the other is xe2x80x94(CH2)q(C3-C8)cycloalkyl, or
Ra and Rb taken together with the carbon to which they are attached form xe2x80x94(C1-C8)alkyl, or 
xe2x80x83or substituted 
xe2x80x83where Axe2x80x94B is  greater than CR4CH2xe2x80x94, D is xe2x80x94CH2xe2x80x94 and R4 is hydrogen, to form product (2), where R3 is 
xe2x80x83or substituted 
xe2x80x83Axe2x80x94B is  greater than CR4CH2xe2x80x94, D is xe2x80x94CH2xe2x80x94 and R4 is hydroxy. At temperatures of about 0xc2x0 C., the reaction is substantially complete in about 10 minutes to an hour.
Dehydration of (2) is achieved using trifluoroacetic acid to prepare product (3) where R3 is xe2x80x94(C2-C6)alkenyl, xe2x80x94(CH2)q(C3-C8)cycloalkyl, 
or substituted 
where Axe2x80x94B is  greater than Cxe2x95x90CHxe2x80x94 and D is xe2x80x94CH2xe2x80x94.
Hydride reduction of (2), preferably using triethylsilane with trifluoroacetic acid or alternately, triethylsilane with a Lewis acid such as boron trifluoride etherate, can be employed to prepare (4), compounds of formula I where R3 or R3xe2x80x2 is 
or substituted 
where Axe2x80x94B is  greater than CR4CH2xe2x80x94, D is xe2x80x94CH2xe2x80x94, and R4 is hydrogen. Alternately, compound (3) can be hydrogenated by refluxing in an alcohol solvent with ammonium formate and palladium on carbon to prepare (4).
In step (b), for compounds where R3 or R3xe2x80x2 is methyl, the lithiated intermediate (1a) is treated with dimethylformamide instead a compound of formula RaCORb.
Compounds of formula I where R3 or R3xe2x80x2 is xe2x80x94(CH2)nO(CH2)pR5, xe2x80x94(CH2)nO(CH2)pR5xe2x80x2 or 
where Axe2x80x94B is  greater than CR4CH2xe2x80x94, D is oxygen, R4 is hydrogen and n is 1 to 4, both inclusive, can be prepared as follows in scheme II. 
Rf is xe2x80x94(CH2)nO(CH2)pR5, 
xe2x80x83or substituted 
xe2x80x83where Axe2x80x94Bxe2x80x94 is  greater than CR4CH2xe2x80x94, D is oxygen and R4 is hydrogen.
Following the procedure outlined in Scheme I, step (a) above, the brominated aminotetralin (1) is first activated by treatment with an organo-lithium reagent, such as n-butyl lithium to form (1a). The activated intermediate (1a) is then C-alkylated with an alkyl halide of the formula XRf where X is a halogen and Rf is xe2x80x94(CH2)nO(CH2)pR5, xe2x80x94(CH2)nO(CH2)pR5xe2x80x2, 
or substituted 
where Axe2x80x94Bxe2x80x94 is  greater than CR4CH2xe2x80x94, D is oxygen and R4 is hydrogen.
When R3 is xe2x80x94(CH2)nO(CH2)pR5 or xe2x80x94(CH2)nO(CH2)pR5xe2x80x2 the halide starting material XRf may be prepared by reacting an appropriately substituted alcohol, HO(CH2)nO(CH2)pR5 or HO(CH2)nO(CH2)pR5xe2x80x2 with methoxymethyl chloride and a base, such as diisopropylethylamine or sodium or potassium carbonate in an organic solvent, such as methylene chloride or chloroform to form the methoxy intermediate. The methoxy group may then be replaced with an appropriate halogen, preferably chlorine, by reacting the intermediate with a halogenating agent such as boron trichloride.
For compounds where R3 or R3xe2x80x2 is 
and D is oxygen, the alkyl halide starting material, XRf, can be prepared by reacting a heterocyclic alkene, 
where r is an integer from 1 to 4 both inclusive, with a halogenating agent, such as hydrogen chloride gas to give 
Compounds of formula I where R3 or R3xe2x80x2 is xe2x80x94(CH2)nO(CH2)pR5 or xe2x80x94(CH2)nO(CH2)pR5xe2x80x2 and n is zero, can be prepared as described in Scheme III as follows. 
An appropriately substituted phenol (6) is O-alkylated with an alkyl halide of the formula X(CH2)pR5 or X(CH2)pR5xe2x80x2 where X is preferably chlorine, in the presence of a base, such as potassium hydroxide or potassium carbonate and a catalyst such as potassium iodide, to form product (7). The reaction is preferably conducted in a solvent, such as ethanol, or solvent system, such as dimethoxyformamide/acetone.
Compounds of formula I may have one or two stereocenters; one at the 2-position of the tetralin ring and the other at the 8-position. Racemates of compounds of formula I, where R3 or R3xe2x80x2 is 
and D is oxygen, may be converted to their respective (R) and (S) enantiomers in a diasteroselective synthesis as described in Scheme IV below. 
Starting material (8) is first treated with methoxymethyl amine and trimethyl aluminum, at temperatures of about xe2x88x9215xc2x0 C. The terminal hydroxy is protected using, for example, butyldiphenylsilane to prepare intermediate (9). Intermediate (9) is then coupled with lithiated starting material (1a), preferably at temperatures of from about xe2x88x9278xc2x0 C. to 0xc2x0 C., in a solvent such as tetrahydrofuran, to prepare (10).
Stereospecific reduction of the carbonyl of (10) can be achieved by treatment with (xe2x88x92)DIP-Cl ((xe2x88x92)dimethylaminoisopropyl chloride) hydrochloride to produce the (R) enantiomer (11). The reaction is preferably conducted at temperatures of about xe2x88x9225xc2x0 C. and is substantially complete in 1 to 3 days.
Protection of the alpha hydroxy can be accomplished by treating (11) with a selective hydroxy-protecting group, such as benzoylchloride, followed by removal of the silyl hydroxy-protecting group on the omega hydroxy, using, for example, tetrabutylammonium fluoride to prepare (12).
Oxidation of the omega hydroxy can then be readily accomplished using pyridinum chlorochromate to prepare (13). Removal of the alpha hydroxy protecting group and cyclization of (13) can then be accomplished by treatment with a strong base, such as sodium hydroxide.
Reduction of (15) is achieved using triethyl silane and trifluoroacetic acid to yield (16).
To achieve the (S) enantiomer, stereospecific reduction of the carbonyl of intermediate (11) can be accomplished using (S)-1,3,3-triphenyltetrahydro-1H,3H-pyrrolo[1,2-C][13,2]oxazaborole and boron trihydride in step (d) Scheme IV above instead of DIP-Cl.
The intermediates and final products may be isolated and purified by conventional techniques, for example by concentration of the solvents, followed by washing of the residue with water, then purification by conventional techniques such as chromatography or recrystallization.
It will be readily appreciated by the skilled artisan that the starting materials which are not described are either commercially available or can be readily prepared by known techniques from commercially available starting materials. All other reactants used to prepare the compounds in the instant invention are commercially available.
The pharmaceutically acceptable acid addition salts are typically formed by reacting an aminotetralin of formula I with an equimolar or excess amount of acid, preferably hydrochloric acid. The reactants are generally combined in a mutual solvent, such as diethyl ether or benzene, and the salt normally precipitates out of solution within about one hour to 10 days, and can be isolated by filtration.